Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2013
Cerebral plasticity and neurological recovery can be stimulated in the ischemic brain by exogenou... more Cerebral plasticity and neurological recovery can be stimulated in the ischemic brain by exogenous pharmacological and cell-based treatments. Neurons, neuroblasts and endothelial cells synergistically interact with each other as a regenerative triad, creating an environment in which neurological recovery takes place. Developmental genetic programs are reactivated. Brain neurons and capillary cells are enabled to sprout, and glial cells support plasticity processes. Until now, the large majority of studies were performed in young, otherwise healthy animals, which lack the risk factors and co-morbidities associated with human stroke. Recent behavioral, histochemical and molecular biological studies have shown that restorative brain responses may differ between young and old animals, and that they are also modulated by vascular risk factors, such as hyperlipidemia and diabetes, which are highly prevalent in ischemic stroke. We claim that age aspects, vascular risk factors and co-morbid...
Aging is associated with a decline of locomotor, sensory and cognitive performance in humans and ... more Aging is associated with a decline of locomotor, sensory and cognitive performance in humans and experimental animals. The rate and pattern of organismal senescence may be regulated in part by changes in multiple genes involved in multiple processes. While this theory is supported by genetic data in lower organisms, a lack of direct experimental evidence in higher organisms has contributed to a broader acceptance of the "stochastic aging" model, in which accumulating, random damaging biological events play an important role. However, these insults alone cannot account for the inexorable deterioration and loss of function that characterizes aging. The higher the complexity of a system, the less obvious is the effect of genetic regulation on aging and the life span, indicating that epigenetic factors play an important role in aging. Most importantly, we present evidence that aging systems do retain some capacity for regeneration and functional recovery after injuries to the ...
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2008
Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain inju... more Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are uncertain. Therefore studying the basic mechanism underlying functional recovery after brain ischemia in aged subjected it is of considerable clinical interest. Potential mechanisms include neuroinflammation, changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Available data indicate that behaviorally, aged rats were more severely impaired by ischemia than were young rats, and they also showed diminished functional recovery. Further, as compared to young rats, aged rats develop a larger infarct area, as well as a necrotic zone characterized by a higher rate of cellular degeneration, and a larger number of apoptotic cells. In both old and young rats, the earl...
Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into ... more Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into the stroke-injured adult rodent brain. How the aged brain responds to grafted iPSCs is unknown. We determined survival and differentiation of grafted human fibroblast-derived iPSCs and their ability to improve recovery in aged rats after stroke. Twenty-four months old rats were subjected to 30 min distal middle cerebral artery occlusion causing neocortical damage. After 48 h, animals were transplanted intracortically with human iPSC-derived long-term neuroepithelial-like stem (hiPSC-lt-NES) cells. Controls were subjected to stroke and were vehicle-injected. Cell-grafted animals performed better than vehicle-injected recipients in cylinder test at 4 and 7 weeks. At 8 weeks, cell proliferation was low (0.7 %) and number of hiPSC-lt-NES cells corresponded to 49.2% of that of implanted cells. Transplanted cells expressed markers of neuroblasts and mature and GABAergic neurons. Cell-grafted r...
Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency pr... more Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency predisposing the patients to infections. Oxidative stress leads to an increased immunoglobulin k light chain production in B cells and contributes to the antibodies' deficiency and hypogammaglobulinemia. Aim of the Study. To evaluate the global oxidative status in patients with CLL and to determine whether the administration of antioxidants decreases complications due to infections. Patients and Method. We studied 84 patients with CLL stratified by Binet staging. Free oxygen radicals and antioxidant status were determined by the FORT and FORD test, respectively, at diagnosis and in the presence of infections. The patients were distributed in two groups: group A, treated only with antileukemic treatment, and group B, treated with antileukemic treatment and antioxidants. Results. By FORD and FORT assay, all patients had at diagnosis a low antioxidant capacity, and high levels of hydroperoxides. Infectious complications were more frequent in group A (B/C stages of disease) than in group B. Administrations of antioxidants stimulated the immune response and decreased infectious complications in CLL. Conclusions. Administrations of antioxidants and a healthy life style may improve the quality of life of patients with CLL and reduce the risk of infectious complications.
The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant m... more The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms. This paper reviews the Janus-faced properties of reactive oxygen species. It will describe the positive aspects of moderately induced ROS but it will also outline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and function in neuropsychiatric diseases, including major depression. A common denominator of all neuropsychiatric diseases including schizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatory agents during development or an accumulation of degenerated neurons, oxidized proteins, glycated products, or lipid peroxidation in the adult brain. Therefore, modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be used to improve neuroprotection in response to oxidative stress. We also discuss the neuroprotective role of the nuclear factor erythroid 2-related factor (Nrf2) in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavenging drugs. The antioxidant therapy is a novel therapeutic strategy. However, the available drugs have pleiotropic actions and are not fully characterized in the clinic. Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies for neuropsychiatric disorders.
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies.... more Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.
Stroke is accompanied by a strong inflammatory reaction in the brain. Periodontal disease is a ch... more Stroke is accompanied by a strong inflammatory reaction in the brain. Periodontal disease is a chronic local infection which causes a systemic low grade inflammation. We hypothesized that a mild systemic inflammatory reaction as caused by periodontal disease prior to stroke onset, may exert a neuroprotective effect in a rat model of focal ischemia.
Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significa... more Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therapeutic interventions.
Chronic hypertension and cerebral amyloid angiopathy (CAA) are the main pathologies which can ind... more Chronic hypertension and cerebral amyloid angiopathy (CAA) are the main pathologies which can induce the rupture of cerebral vessels and intracerebral hemorrhages, as a result of degenerative changes in the vascular wall. A lot of progress has been made in this direction since the successful creation of the first mouse model for the study of Alzheimer's disease (AD), as the spectrum of AD pathology includes a plethora of changes found in pure cerebrovascular diseases. We describe here some of these mouse models having important vascular changes that parallel human AD pathology, and more importantly, we show how these models have helped us understand more about the mechanisms that lead to CAA formation. An important cellular event associated with reduced structural and functional recovery after stroke in aged animals is the early formation of a scar in the infarcted region that impairs subsequent neural recovery and repair. We review recent evidence showing that the rapid formation of the glial scar following stroke in aged rats is associated with premature cellular proliferation that originates primarily from the walls of capillaries in the corpus callosum adjacent to the infarcted region. After stroke several vascular mechanisms are turned-on immediately to protect the brain from further damage and help subsequent neuroregeneration and functional recovery. Although does occur after stroke, vasculogenesis is overshadowed in its protective/restorative role by the angiogenesis and arteriogenesis. Understanding the basic mechanisms underlying functional recovery after cerebral stroke in aging subjects is likely to yield new insights into the treatment of brain injury in the clinic.
Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain a... more Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain accompanied by altered bowel habits. Although generally considered a functional disorder, there is now substantial evidence that IBS is associated with a poor quality of life and significant negative impact on work and social domains. Neuroimaging studies documented changes in the prefrontal cortex, ventro-lateral and posterior parietal cortex and thalami, and implicate alteration of brain circuits involved in attention, emotion and pain modulation. Emerging data reveals the interaction between psychiatric disorders including generalized anxiety disorder, panic disorder, major depressive disorder, bipolar disorder, and schizophrenia and IBS, which suggests that this association should not be ignored when developing strategies for screening and treatment. Psychological, social and genetic factors appear to be important in the development of IBS symptomatology through several mechanisms: alteration of HPA axis modulation, enhanced perception of visceral stimuli or psychological vulnerability. Elucidating the molecular mechanisms of IBS with or without psychiatric comorbidities is crucial for elucidating the pathophysiology and for the identification of new therapeutical targets in IBS.
Ageing is associated with changes in the function of various organ systems. Changes in the cardio... more Ageing is associated with changes in the function of various organ systems. Changes in the cardiovascular system affect both directly and indirectly the function in a variety of organs, including the brain, with consequent neurological (motor and sensory performance) and cognitive impairments, as well as leading to the development of various psychiatric diseases. Post-stroke depression (PSD) is among the most frequent neuropsychiatric consequences of cerebral ischemia. This review discusses several animal models used for the study of PSD and summarizes recent findings in the genomic profile of the ageing brain, which are associated with age-related disorders in the elderly. Since stroke and depression are diseases with increased incidence in the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD. Finally, we discuss the relationship between ageing, circadian rhythmicity and PSD.
Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods ... more Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (10(6) cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the "islet of regeneration." However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.
Background: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogene... more Background: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogenesis can only be assessed in postmortem tissue, its functional significance remains undetermined, and identifying an in vivo correlate of neurogenesis has become an important goal. By studying pentylenetetrazole-induced brain stimulation in a rat model of kindling we accidentally discovered that 2561 days periodic stimulation of Sprague-Dawley rats led to a highly efficient increase in seizure susceptibility.
Background: Because most human stroke victims are elderly, studies of experimental stroke in the ... more Background: Because most human stroke victims are elderly, studies of experimental stroke in the aged rather than the young rat model may be optimal for identifying clinically relevant cellular responses, as well for pinpointing beneficial interventions.
In aged humans, stroke is a major cause of disability for which no neuroprotective measures are a... more In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. A viable alternative to conventional drug-based neuroprotective therapies is brain/body cooling, or hypothermia. In animal studies of focal ischemia, short-term hypothermia consistently reduces infarct size. Nevertheless, efficient neuroprotection requires long-term, regulated lowering of whole body temperature. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 17-month-old male Sprague-Dawley rats. After stroke, the aged rats were exposed for 2 days to a mixture of air and a mild inhibitor of oxidative phosphorylation, hydrogen sulfide (H(2)S), which resulted in sustained, deep hypothermia (30.8+/-0.7 degrees C). Long-term hypothermia led to a 50% reduction in infarct size with a concomitant reduction in the number of phagocytic cells. At the transcription level, hypothermia caused a reduction in the mRNA coding for caspase 12, NF-kappa B and grp78 in the peri-infarcted region, suggesting an overall decrease in the transcriptional activity related to inflammation and apoptosis. Behaviorally, hypothermia was associated with better performance on tests that require complex sensorimotor skills, in the absence of obvious neurological deficits or physiological side effects, in aged rats. Prolonged, H(2)S-induced hypothermia is a simple and efficacious method to limit the damage inflicted by stroke in aged rats.
Alzheimer's disease (AD) belongs to a group of neurodegenerative disorders. It is characterized b... more Alzheimer's disease (AD) belongs to a group of neurodegenerative disorders. It is characterized by irreversible and progressive memory loss accompanied with decline in other cognitive functions. There is convincing evidence that inflammatory response to accumulation of beta amyloid plays a pivotal role in the progression of neuropathological changes found in AD. As AD affects millions of patients worldwide, the issues concerning diagnosis and treatment are particularly important. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP), a novel neuropeptide, shows pleiotropic effects with antiinflammatory and neuroprotective properties. Current research was directed at assessing PACAP plasma levels in AD. Twenty-eight women with moderate to severe stadium of AD (aged 73.54 yrs ± 3.98; MMSE 10.75 ± 4.18) and 67 women without dementia (aged 72.85 yrs ± 5.64) were enrolled in the study. After clinical examination that excluded the presence of inflammatory process, the blood was collected for evaluating PACAP as well as Interleukin 6 (IL-6) level as a marker of inflammation. Plasma PACAP and IL-6 levels were estimated using radioimmunoassay (RIA) and ELISA methods, respectively. Comparisons were analyzed with unpaired t-Student test. Significantly higher values of PACAP were found in AD group as compared with control group (88.1 pg/ml ± 1.31 vs. 56.4 pg/ml ± 4.21), p < 0.01. The proinflammatory activity in plasma of AD patients was confirmed by enhanced IL-6 levels (6.63 pg/ ml ± 0.95 vs. 2.27 pg/ml ± 0.2, p < 0.01). We conclude that there is a significant increase in PACAP plasma levels in moderate/severe AD. It could be suggested that PACAP may influence the AD course.
Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain inju... more Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only partly understood. Therefore, studying the basic mechanisms underlying structural and functional recovery after brain injury in aged subjects is of considerable clinical interest. Behavioral and cytological analyses of rodents that have undergone experimental injury show that: (a) behaviorally, aged rodents are more severely impaired by ischemia than are young animals, and older rodents also show diminished functional recovery; (b) compared to young animals, aged animals develop a larger infarct area, as well as a necrotic zone characterized by a higher rate of cellular degeneration and a larger number of apoptotic cells; (c) both astrocytes and macrophages are activated strongly and early following stroke in aged rodents; (d) in older animals, the premature, intense cytoproliferative activity following brain injury leads to the precipitous formation of growth-inhibiting scar tissue, a phenomenon amplified by the persistent expression of neurotoxic factors; (e) though the timing is altered, the regenerative capability of the brain is largely preserved in rats, at least into early old age. Whether endogenous neurogenesis contributes to spontaneous recovery after stroke has not yet been established. If neurogenesis from endogenous neuronal stem cells is to be used therapeutically, an individual approach will be required to assess the possible extent of neurogenic response as well as the possibilities to alter this response for functional improvement or prevention of further loss of brain function.
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2013
Cerebral plasticity and neurological recovery can be stimulated in the ischemic brain by exogenou... more Cerebral plasticity and neurological recovery can be stimulated in the ischemic brain by exogenous pharmacological and cell-based treatments. Neurons, neuroblasts and endothelial cells synergistically interact with each other as a regenerative triad, creating an environment in which neurological recovery takes place. Developmental genetic programs are reactivated. Brain neurons and capillary cells are enabled to sprout, and glial cells support plasticity processes. Until now, the large majority of studies were performed in young, otherwise healthy animals, which lack the risk factors and co-morbidities associated with human stroke. Recent behavioral, histochemical and molecular biological studies have shown that restorative brain responses may differ between young and old animals, and that they are also modulated by vascular risk factors, such as hyperlipidemia and diabetes, which are highly prevalent in ischemic stroke. We claim that age aspects, vascular risk factors and co-morbid...
Aging is associated with a decline of locomotor, sensory and cognitive performance in humans and ... more Aging is associated with a decline of locomotor, sensory and cognitive performance in humans and experimental animals. The rate and pattern of organismal senescence may be regulated in part by changes in multiple genes involved in multiple processes. While this theory is supported by genetic data in lower organisms, a lack of direct experimental evidence in higher organisms has contributed to a broader acceptance of the "stochastic aging" model, in which accumulating, random damaging biological events play an important role. However, these insults alone cannot account for the inexorable deterioration and loss of function that characterizes aging. The higher the complexity of a system, the less obvious is the effect of genetic regulation on aging and the life span, indicating that epigenetic factors play an important role in aging. Most importantly, we present evidence that aging systems do retain some capacity for regeneration and functional recovery after injuries to the ...
Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie, 2008
Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain inju... more Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are uncertain. Therefore studying the basic mechanism underlying functional recovery after brain ischemia in aged subjected it is of considerable clinical interest. Potential mechanisms include neuroinflammation, changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Available data indicate that behaviorally, aged rats were more severely impaired by ischemia than were young rats, and they also showed diminished functional recovery. Further, as compared to young rats, aged rats develop a larger infarct area, as well as a necrotic zone characterized by a higher rate of cellular degeneration, and a larger number of apoptotic cells. In both old and young rats, the earl...
Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into ... more Induced pluripotent stem cells (iPSCs) improve behavior and form neurons after implantation into the stroke-injured adult rodent brain. How the aged brain responds to grafted iPSCs is unknown. We determined survival and differentiation of grafted human fibroblast-derived iPSCs and their ability to improve recovery in aged rats after stroke. Twenty-four months old rats were subjected to 30 min distal middle cerebral artery occlusion causing neocortical damage. After 48 h, animals were transplanted intracortically with human iPSC-derived long-term neuroepithelial-like stem (hiPSC-lt-NES) cells. Controls were subjected to stroke and were vehicle-injected. Cell-grafted animals performed better than vehicle-injected recipients in cylinder test at 4 and 7 weeks. At 8 weeks, cell proliferation was low (0.7 %) and number of hiPSC-lt-NES cells corresponded to 49.2% of that of implanted cells. Transplanted cells expressed markers of neuroblasts and mature and GABAergic neurons. Cell-grafted r...
Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency pr... more Chronic lymphocytic leukemia (CLL) is characterized by a predominant humoral immune deficiency predisposing the patients to infections. Oxidative stress leads to an increased immunoglobulin k light chain production in B cells and contributes to the antibodies&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; deficiency and hypogammaglobulinemia. Aim of the Study. To evaluate the global oxidative status in patients with CLL and to determine whether the administration of antioxidants decreases complications due to infections. Patients and Method. We studied 84 patients with CLL stratified by Binet staging. Free oxygen radicals and antioxidant status were determined by the FORT and FORD test, respectively, at diagnosis and in the presence of infections. The patients were distributed in two groups: group A, treated only with antileukemic treatment, and group B, treated with antileukemic treatment and antioxidants. Results. By FORD and FORT assay, all patients had at diagnosis a low antioxidant capacity, and high levels of hydroperoxides. Infectious complications were more frequent in group A (B/C stages of disease) than in group B. Administrations of antioxidants stimulated the immune response and decreased infectious complications in CLL. Conclusions. Administrations of antioxidants and a healthy life style may improve the quality of life of patients with CLL and reduce the risk of infectious complications.
The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant m... more The brain is a major metabolizer of oxygen and yet has relatively feeble protective antioxidant mechanisms. This paper reviews the Janus-faced properties of reactive oxygen species. It will describe the positive aspects of moderately induced ROS but it will also outline recent research findings concerning the impact of oxidative and nitrooxidative stress on neuronal structure and function in neuropsychiatric diseases, including major depression. A common denominator of all neuropsychiatric diseases including schizophrenia and ADHD is an increased inflammatory response of the brain caused either by an exposure to proinflammatory agents during development or an accumulation of degenerated neurons, oxidized proteins, glycated products, or lipid peroxidation in the adult brain. Therefore, modulation of the prooxidant-antioxidant balance provides a therapeutic option which can be used to improve neuroprotection in response to oxidative stress. We also discuss the neuroprotective role of the nuclear factor erythroid 2-related factor (Nrf2) in the aged brain in response to oxidative stressors and nanoparticle-mediated delivery of ROS-scavenging drugs. The antioxidant therapy is a novel therapeutic strategy. However, the available drugs have pleiotropic actions and are not fully characterized in the clinic. Additional clinical trials are needed to assess the risks and benefits of antioxidant therapies for neuropsychiatric disorders.
Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies.... more Stroke has limited treatment options, demanding a vigorous search for new therapeutic strategies. Initial enthusiasm to stimulate restorative processes in the ischemic brain by means of cell-based therapies has meanwhile converted into a more balanced view recognizing impediments related to unfavorable environments that are in part related to aging processes. Since stroke afflicts mostly the elderly, it is highly desirable and clinically important to test the efficacy of cell therapies in aged brain microenvironments. Although widely believed to be refractory to regeneration, recent studies using both neural precursor cells and bone marrow-derived mesenchymal stem cells for stroke therapy suggest that the aged rat brain is not refractory to cell-based therapy, and that it also supports plasticity and remodeling. Yet, important differences exist in the aged compared with young brain, i.e., the accelerated progression of ischemic injury to brain infarction, the reduced rate of endogenous neurogenesis and the delayed initiation of neurological recovery. Pitfalls in the development of cell-based therapies may also be related to age-associated comorbidities, e.g., diabetes or hyperlipidemia, which may result in maladaptive or compromised brain remodeling, respectively. These age-related aspects should be carefully considered in the clinical translation of restorative therapies.
Stroke is accompanied by a strong inflammatory reaction in the brain. Periodontal disease is a ch... more Stroke is accompanied by a strong inflammatory reaction in the brain. Periodontal disease is a chronic local infection which causes a systemic low grade inflammation. We hypothesized that a mild systemic inflammatory reaction as caused by periodontal disease prior to stroke onset, may exert a neuroprotective effect in a rat model of focal ischemia.
Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significa... more Major depressive disorder (MDD) is a severe psychiatric illness that is associated with significant morbidity and mortality. Despite advances in the treatment of major depression, one-third of depressed patients fail to respond to conventional antidepressant medication. One pathophysiologic mechanism hypothesized to contribute to treatment resistance in depression is inflammation. Inflammation has been linked to depression by a number of putative mechanisms involving perfusion deficits that can trigger microglial activation and subsequent neuroinflammation in the elderly. However, the pathophysiological mechanisms remain to be further elucidated. This review focusses on recent studies addressing the complex relationships between depression, aging, inflammation and perfusion deficits in the elderly. We expect that a better understanding of neuroinflammatory mechanisms associated with age-related diseases may lead to the discovery of new biomarkers of MDD and development of new therapeutic interventions.
Chronic hypertension and cerebral amyloid angiopathy (CAA) are the main pathologies which can ind... more Chronic hypertension and cerebral amyloid angiopathy (CAA) are the main pathologies which can induce the rupture of cerebral vessels and intracerebral hemorrhages, as a result of degenerative changes in the vascular wall. A lot of progress has been made in this direction since the successful creation of the first mouse model for the study of Alzheimer&#39;s disease (AD), as the spectrum of AD pathology includes a plethora of changes found in pure cerebrovascular diseases. We describe here some of these mouse models having important vascular changes that parallel human AD pathology, and more importantly, we show how these models have helped us understand more about the mechanisms that lead to CAA formation. An important cellular event associated with reduced structural and functional recovery after stroke in aged animals is the early formation of a scar in the infarcted region that impairs subsequent neural recovery and repair. We review recent evidence showing that the rapid formation of the glial scar following stroke in aged rats is associated with premature cellular proliferation that originates primarily from the walls of capillaries in the corpus callosum adjacent to the infarcted region. After stroke several vascular mechanisms are turned-on immediately to protect the brain from further damage and help subsequent neuroregeneration and functional recovery. Although does occur after stroke, vasculogenesis is overshadowed in its protective/restorative role by the angiogenesis and arteriogenesis. Understanding the basic mechanisms underlying functional recovery after cerebral stroke in aging subjects is likely to yield new insights into the treatment of brain injury in the clinic.
Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain a... more Irritable bowel syndrome (IBS) is a functional syndrome characterized by chronic abdominal pain accompanied by altered bowel habits. Although generally considered a functional disorder, there is now substantial evidence that IBS is associated with a poor quality of life and significant negative impact on work and social domains. Neuroimaging studies documented changes in the prefrontal cortex, ventro-lateral and posterior parietal cortex and thalami, and implicate alteration of brain circuits involved in attention, emotion and pain modulation. Emerging data reveals the interaction between psychiatric disorders including generalized anxiety disorder, panic disorder, major depressive disorder, bipolar disorder, and schizophrenia and IBS, which suggests that this association should not be ignored when developing strategies for screening and treatment. Psychological, social and genetic factors appear to be important in the development of IBS symptomatology through several mechanisms: alteration of HPA axis modulation, enhanced perception of visceral stimuli or psychological vulnerability. Elucidating the molecular mechanisms of IBS with or without psychiatric comorbidities is crucial for elucidating the pathophysiology and for the identification of new therapeutical targets in IBS.
Ageing is associated with changes in the function of various organ systems. Changes in the cardio... more Ageing is associated with changes in the function of various organ systems. Changes in the cardiovascular system affect both directly and indirectly the function in a variety of organs, including the brain, with consequent neurological (motor and sensory performance) and cognitive impairments, as well as leading to the development of various psychiatric diseases. Post-stroke depression (PSD) is among the most frequent neuropsychiatric consequences of cerebral ischemia. This review discusses several animal models used for the study of PSD and summarizes recent findings in the genomic profile of the ageing brain, which are associated with age-related disorders in the elderly. Since stroke and depression are diseases with increased incidence in the elderly, great clinical benefit may especially accrue from deciphering and targeting basic mechanisms underlying PSD. Finally, we discuss the relationship between ageing, circadian rhythmicity and PSD.
Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods ... more Attractive therapeutic strategies to enhance post-stroke recovery of aged brains include methods of cellular therapy that can enhance the endogenous restorative mechanisms of the injured brain. Since stroke afflicts mostly the elderly, it is highly desirable to test the efficacy of cell therapy in the microenvironment of aged brains that is generally refractory to regeneration. In particular, stem cells from the bone marrow allow an autologous transplantation approach that can be translated in the near future to the clinical practice. Such a bone marrow-derived therapy includes the grafting of stem cells as well as the delayed induction of endogenous stem cell mobilization and homing by the stem cell mobilizer granulocyte colony-stimulating factor (G-CSF). We tested the hypothesis that grafting of bone marrow-derived pre-differentiated mesenchymal cells (BM-MSCs) in G-CSF-treated animals improves the long-term functional outcome in aged rodents. To this end, G-CSF alone (50 μg/kg) or in combination with a single dose (10(6) cells) of rat BM MSCs was administered intravenously to Sprague-Dawley rats at 6 h after transient occlusion (90 min) of the middle cerebral artery. Infarct volume was measured by magnetic resonance imaging at 3 and 48 days post-stroke and additionally by immunhistochemistry at day 56. Functional recovery was tested during the entire post-stroke survival period of 56 days. Daily treatment for post-stroke aged rats with G-CSF led to a robust and consistent improvement of neurological function after 28 days. The combination therapy also led to robust angiogenesis in the formerly infarct core and beyond in the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;islet of regeneration.&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; However, G-CSF + BM MSCs may not impact at all on the spatial reference-memory task or infarct volume and therefore did not further improve the post-stroke recovery. We suggest that in a real clinical practice involving older post-stroke patients, successful regenerative therapies would have to be carried out for a much longer time.
Background: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogene... more Background: Neurogenesis persists throughout life in the adult mammalian brain. Because neurogenesis can only be assessed in postmortem tissue, its functional significance remains undetermined, and identifying an in vivo correlate of neurogenesis has become an important goal. By studying pentylenetetrazole-induced brain stimulation in a rat model of kindling we accidentally discovered that 2561 days periodic stimulation of Sprague-Dawley rats led to a highly efficient increase in seizure susceptibility.
Background: Because most human stroke victims are elderly, studies of experimental stroke in the ... more Background: Because most human stroke victims are elderly, studies of experimental stroke in the aged rather than the young rat model may be optimal for identifying clinically relevant cellular responses, as well for pinpointing beneficial interventions.
In aged humans, stroke is a major cause of disability for which no neuroprotective measures are a... more In aged humans, stroke is a major cause of disability for which no neuroprotective measures are available. A viable alternative to conventional drug-based neuroprotective therapies is brain/body cooling, or hypothermia. In animal studies of focal ischemia, short-term hypothermia consistently reduces infarct size. Nevertheless, efficient neuroprotection requires long-term, regulated lowering of whole body temperature. Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 17-month-old male Sprague-Dawley rats. After stroke, the aged rats were exposed for 2 days to a mixture of air and a mild inhibitor of oxidative phosphorylation, hydrogen sulfide (H(2)S), which resulted in sustained, deep hypothermia (30.8+/-0.7 degrees C). Long-term hypothermia led to a 50% reduction in infarct size with a concomitant reduction in the number of phagocytic cells. At the transcription level, hypothermia caused a reduction in the mRNA coding for caspase 12, NF-kappa B and grp78 in the peri-infarcted region, suggesting an overall decrease in the transcriptional activity related to inflammation and apoptosis. Behaviorally, hypothermia was associated with better performance on tests that require complex sensorimotor skills, in the absence of obvious neurological deficits or physiological side effects, in aged rats. Prolonged, H(2)S-induced hypothermia is a simple and efficacious method to limit the damage inflicted by stroke in aged rats.
Alzheimer's disease (AD) belongs to a group of neurodegenerative disorders. It is characterized b... more Alzheimer's disease (AD) belongs to a group of neurodegenerative disorders. It is characterized by irreversible and progressive memory loss accompanied with decline in other cognitive functions. There is convincing evidence that inflammatory response to accumulation of beta amyloid plays a pivotal role in the progression of neuropathological changes found in AD. As AD affects millions of patients worldwide, the issues concerning diagnosis and treatment are particularly important. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP), a novel neuropeptide, shows pleiotropic effects with antiinflammatory and neuroprotective properties. Current research was directed at assessing PACAP plasma levels in AD. Twenty-eight women with moderate to severe stadium of AD (aged 73.54 yrs ± 3.98; MMSE 10.75 ± 4.18) and 67 women without dementia (aged 72.85 yrs ± 5.64) were enrolled in the study. After clinical examination that excluded the presence of inflammatory process, the blood was collected for evaluating PACAP as well as Interleukin 6 (IL-6) level as a marker of inflammation. Plasma PACAP and IL-6 levels were estimated using radioimmunoassay (RIA) and ELISA methods, respectively. Comparisons were analyzed with unpaired t-Student test. Significantly higher values of PACAP were found in AD group as compared with control group (88.1 pg/ml ± 1.31 vs. 56.4 pg/ml ± 4.21), p < 0.01. The proinflammatory activity in plasma of AD patients was confirmed by enhanced IL-6 levels (6.63 pg/ ml ± 0.95 vs. 2.27 pg/ml ± 0.2, p < 0.01). We conclude that there is a significant increase in PACAP plasma levels in moderate/severe AD. It could be suggested that PACAP may influence the AD course.
Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain inju... more Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only partly understood. Therefore, studying the basic mechanisms underlying structural and functional recovery after brain injury in aged subjects is of considerable clinical interest. Behavioral and cytological analyses of rodents that have undergone experimental injury show that: (a) behaviorally, aged rodents are more severely impaired by ischemia than are young animals, and older rodents also show diminished functional recovery; (b) compared to young animals, aged animals develop a larger infarct area, as well as a necrotic zone characterized by a higher rate of cellular degeneration and a larger number of apoptotic cells; (c) both astrocytes and macrophages are activated strongly and early following stroke in aged rodents; (d) in older animals, the premature, intense cytoproliferative activity following brain injury leads to the precipitous formation of growth-inhibiting scar tissue, a phenomenon amplified by the persistent expression of neurotoxic factors; (e) though the timing is altered, the regenerative capability of the brain is largely preserved in rats, at least into early old age. Whether endogenous neurogenesis contributes to spontaneous recovery after stroke has not yet been established. If neurogenesis from endogenous neuronal stem cells is to be used therapeutically, an individual approach will be required to assess the possible extent of neurogenic response as well as the possibilities to alter this response for functional improvement or prevention of further loss of brain function.
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Papers by Ana-maria Buga